NIH Panel Sets Standards for Adjuvant Breast Cancer Therapy

NIH Panel Sets Standards for Adjuvant Breast Cancer Therapy

BETHESDACombination chemotherapy as an adjuvant treatment for
breast cancer yields long-term survival benefits and should be
offered to patients, even those whose tumors have not spread beyond
the breast, according to a consensus panel convened by the National
Institutes of Health. The panel also recommended hormone therapy for
women whose tumors have hormone receptors, and radiation therapy for
women who have had a mastectomy and are at high risk of recurrence.

Women with breast cancer face a growing list of effective options for
adjuvant treatment, due to the successful completion of several
large, randomized clinical trials, said panel chair Patricia Eifel,
MD, of M.D. Anderson Cancer Center.

Since the previous NIH Consensus Development Conference on this
topic, held in 1990, more compelling evidence has amassed on the
long-term advantage of chemotherapy and the advantages of tamoxifen
(Nolvadex) for cancers with estrogen receptors. The duration of
the advantage is maintained for 15 years, Dr. Eifel said.

NIH Consensus Development Conferences utilize an independent,
non-Federal panel to weigh the scientific evidence and establish a
consensus. This conference addressed only operable, invasive breast
cancer. It did not cover metastatic disease or ductal carcinoma in
situ (DCIS). It also focused exclusively on adjuvant treatments.

Very few new prognostic or predictive factors for breast cancer have
been validated in the last 10 years. The accepted factors used for
selecting adjuvant therapy for breast cancer, the panel said, are
age, tumor size, axillary node status, histology, standardized
pathologic grade, and hormone-receptor status.

Overexpression of HER-2, p53 status, histologic evidence of vascular
invasion, and quantitative parameters of angiogenesis have exciting
potential, the panel stated, but their role in patient management is
not yet established. Also, the panel said, the clinical significance
of sentinel lymph node biopsy and of sensitive assays for
micrometastatic disease in nodes or bone marrow remain uncertain.

Adjuvant chemotherapy, with two or more agents, substantially
improves long-term relapse-free and overall survival, and should be
recommended to the majority of women with localized breast cancer,
regardless of nodal, menopausal, or hormone-receptor status, the
panel said. Four to six courses appears optimal.

Anthracyclines, such as doxorubicin and epirubicin (Ellence), added
to adjuvant chemotherapy regimens result in a small but significant
improvement in survival, compared with non-anthracycline-containing
regimens. The risk of excessive cardiotoxicity with anthracycline use
appears to be limited to women who have significant preexisting heart
disease.

The panel stated that all women whose tumors are hormone-receptor
positive should receive 5 years of tamoxifen, regardless of their
age, menopausal status, tumor size, or nodal status. Tamoxifen
therapy has led to substantial reductions in tumor recurrence, second
primary breast cancers, and death.

If a womans hormone-receptor status is unknown, she should be
considered receptor positive and offered tamoxifen. HER-2 status
should not influence the decision to recommend hormone therapy.

Women who have undergone mastectomy and who have four or more
cancerous lymph nodes or an advanced primary tumor would benefit from
postsurgical radiation.

Panel member Carolyn B. Hendricks, MD, a medical oncologist at
Suburban Specialty Care Physicians, Bethesda, said that
postmastectomy radiation is one area where the panels
conclusions should change current practice.

The panel also recommended ovarian ablation for premenopausal
patients who are hormone-receptor positive. Although it is not
frequently used in the United States, ovarian ablation through
surgery, radiation to the ovaries, or temporary chemical suppression
of ovarian function appears to produce a benefit similar to that of
cyclophosphamide, metho-trexate, fluorouracil (CMF) chemotherapy.
Combining it with chemotherapy offers no benefit.

Having the option of offering temporary ovarian ablation to young
women who look forward to childbearing, is an important step forward,
Dr. Hendricks said.

Although few studies have included breast cancer patients age 70
years or older, the panel pointed out that these women frequently
have tumors with estrogen-receptor protein and have a high likelihood
of response to hormone therapy. They are also likely to experience a
survival benefit from chemotherapy, but information on toxicities and
the effect of comorbid conditions is unavailable.

Noting that more than half of new breast cancers occur in women 65
years and older, the panel stated that studies addressing the value
and tolerance of adjuvant therapies in women over age 70 are urgently needed.

What Not to Offer

The consensus panel also pointed out what clinicians should not
be offering to their patients. For example, tamoxifen should not be
given to women with hormone-receptor-negative disease. Also, there is
no evidence yet that combining hormonal treatments, such as tamoxifen
and raloxifene (Evista), is beneficial.

Taxanes are used more widely than this statement would maybe
recommend, said panel member Walter J. Curran, Jr., MD,
professor and chairman, Department of Radiation Oncology, Thomas
Jefferson University Hospital.

Although taxanespaclitaxel (Taxol) and docetaxel
(Taxotere)have demonstrated benefit for metastatic breast
cancer, the panel was not convinced of their utility for earlier
disease. The panel called the data on taxanes for node-positive
breast cancer inconclusive and recommended that taxanes
not be used in node-negative patients outside of randomized clinical
trials.

The decision whether to provide adjuvant therapy for women with
node-negative cancers smaller than 1 cm is difficult and should be
individualized. Several studies have shown that 8-year survival for
these patients is greater than 90%. The small benefits derived from
adjuvant therapies should be weighed against potential toxicities.

The panel went further to say that patients with small, node-negative
breast cancers with favorable histologic subtypes, such as tubular
and mucinous cancers, do very well over the long-term without
adjuvant chemotherapy following primary treatment.

As women with breast cancer face more treatment options, decision
making becomes a more complex process for patients and their
physicians, Dr. Eifel said. The panel recommended the development and
evaluation of decision aids and other techniques to improve
patients involvement and understanding of treatment decisions.

Noting that fewer than 3% of cancer patients are treated in clinical
trials, the panel called for improvements in patient and physician
participation in prospective randomized studies.

The risks and benefits of new selective estrogen-receptor modulators
(SERMs) and aromatase inhibitors in the adjuvant setting should be
examined as well.

Current randomized trials of high-dose chemotherapy and of taxanes
need to be completed to determine their role in the standard
management of breast cancer. The panel recommended further study of
therapies considered promising, such as trastuzumab (Herceptin),
bisphosphonates, and antiangiogenesis compounds.

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